Entamoeba histolytica is an important human pathogen with significant impact on a global scale. E. histolytica infects 500 million people annually, causes invasive disease in 50 million people and results in 100,000 deaths making it a leading parasitic cause of death worldwide. Despite the human burden of amebiasis there is a paucity of antimicrobials available, with treatment dependent on a single class of agents and emergence of resistance an ongoing concern. Additionally, there are no significant pipelines for novel drug development against this neglected tropical disease. Thus, there is a critical need for new drugs against Entamoeba. To circumvent the long and costly standard drug development route, we chose a compound screening approach based on phenotypic readouts of cell viability and stage conversion. The libraries we will screen have two advantages: previous success in parasitic systems and largely from repurposed FDA-approved compounds. These advantages combined with the drug development expertise at Stanford predict a successful outcome. We propose the following: Aim 1: Drug screen against Entamoeba trophozoites and encystation (early cysts); and Aim 2 Confirmation of select hits. Successful completion of these aims will identify lead compounds/series with activity against Entamoeba. These compounds will give insights into the cell biology of Entamoeba development and eventually can also provide a beginning pipeline for drug development efforts. Based on our experience with Entamoeba development and a cadre of outstanding colleagues and collaborators, we are confident of a successful outcome.